Prenatal bystander stress alters brain, behavior, and the epigenome of developing rat offspring.

The prenatal environment, including prenatal stress, has been extensively studied in laboratory animals and humans. However, studies of the prenatal environment usually directly stress pregnant females, but stress may come 'indirectly', through stress to a cage-mate. The current study used indirect prenatal bystander stress and investigated the effects on the gross morphology, pre-weaning behavior, and epigenome of rat offspring. Pregnant Long-Evans rats were housed with another female rat that underwent elevated platform stress from gestational days 12 to 16. We found that ultrasonic vocalizations of female cage-mates were disrupted following the stress procedure. After birth, offspring were tested on two behavioral tasks and sacrificed at postnatal day 21 (p21). Frontal cortex and hippocampal tissue was used to measure global DNA methylation and gene expression changes. At p21, bystander-stressed female offspring exhibited increased body weight. Offspring behavior on the negative geotaxis task was altered by prenatal bystander stress, and locomotor behavior was reduced in female offspring. Global DNA methylation increased in the frontal cortex and hippocampus of bystander-stressed offspring. Microarray analysis revealed significant gene expression level changes in 558 different genes, of which only 10 exhibited overlap between males and females or brain areas. These alterations in gene expression were associated with overrepresentation of 36 biological processes and 34 canonical pathways. Prenatal stress thus does not have to be experienced by the mother herself to influence offspring brain development. Furthermore, this type of 'indirect' prenatal stress alters offspring DNA methylation patterns, gene expression profiles, and behavior.